Inhibitors for treating diseases characterized by atrial enlargement or remodeling

ABSTRACT

The present invention relates to the NEP inhibitor pro-drug N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, or a pharmaceutically acceptable salt thereof; or the NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid, or a pharmaceutically acceptable salt thereof, pro-drug for use in the treatment, prevention or delay of progression of a disease characterized by atrial enlargement and/or remodeling; a method for treatment, prevention or delay of progression of a disease characterized by atrial enlargement and/or remodeling comprising administration of a therapeutically effective amount, or a prophylactically effective amount, of the NEP inhibitor or the NEP inhibitor pro-drug, or a pharmaceutically acceptable salt pro-drug thereof, to a subject, e.g. a human subject, in need of such treatment. The present invention further relates to a pharmaceutical composition or a commercial package comprising the NEP inhibitor or the NEP inhibitor pro-drug, or a pharmaceutically acceptable salt thereof, pro-drug for use in the treatment, prevention or delay of progression of a disease characterized by atrial enlargement and/or remodeling.

The present invention relates to the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester, or a pharmaceutically acceptable salt thereof; or theNEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or a pharmaceutically acceptable salt thereof, pro-drug for use inthe treatment, prevention or delay of progression of a diseasecharacterized by atrial enlargement and/or remodeling; a method fortreatment, prevention or delay of progression of a disease characterizedby atrial enlargement and/or remodeling comprising administration of atherapeutically effective amount, or a prophylactically effectiveamount, of the NEP inhibitor or the NEP inhibitor pro-drug, or apharmaceutically acceptable salt pro-drug thereof, to a subject, e.g. ahuman subject, in need of such treatment. The present invention furtherrelates to a pharmaceutical composition or a commercial packagecomprising the NEP inhibitor or the NEP inhibitor pro-drug, or apharmaceutically acceptable salt thereof, pro-drug for use in thetreatment, prevention or delay of progression of a disease characterizedby atrial enlargement and/or remodeling.

BACKGROUND OF THE INVENTION

Cardiovascular (CV) disease is the leading cause of death in the westernworld. The increase in CV disease has not only led to an increase inmortality but an increase in CV morbidity. One of the major forms of CVmorbidity is heart failure (HF). HF is a complex clinical syndromecharacterized by high mortality, frequent hospitalization, poor qualityof life, and a complex therapeutic regimen. In the US alone, HF affectsnearly 5 million people and there are an estimated 400,000 newlydiagnosed cases annually (American Heart Association, 2006, HeartDisease and Stroke Statistics, 2006 Update, Dallas, Tex.). HF isresponsible for more hospitalizations than all forms of cancer combinedand is the leading cause of hospitalization in patients older than 65years of age (American Heart Association, 2006, Heart Disease and StrokeStatistics, 2006 Update, Dallas, Tex.; Adams et al., 2006, J CardiacFail, 12(1):10-38.). In-hospital mortality is excessive and readmissionis distressingly common, despite advances in pharmacological and devicetherapies. This need for increased hospitalizations results in enormousdirect costs and more is spent annually on the diagnosis and treatmentof HF by Medicare than on any other Medicare diagnosis (American HeartAssociation, 2006, Heart Disease and Stroke Statistics, 2006 Update,Dallas, Tex.; Adams et al., 2006, J Cardiac Fail, 12(1):10-38.). HF isclassified as HF with reduced ejection fraction (HF-REF) versus HF withpreserved ejection fraction (HF-PEF).

Therapies targeted at improving outcomes in HF-REF have been wellstudied over the past two decades leading to an improvement inmorbidity, mostly in the form of a decrease in re-hospitalization forHF-REF with angiotensin converting enzyme (ACE) inhibitors, angiotensinreceptor blockers (ARBs) and β blockers (Cohn et al., 1991, N Engl JMed, 325:303-310; Pfeffer et al., 2003, Lancet, 362:759-766; TheCONSENSUS Trial Study Group, 1987, N Engl J Med, 316:1429-1435; TheSOLVD Investigators, 1992, N Engl J Med, 327:685-691; The SOLVDInvestigators, 1991, N Engl J Med, 325:293-302; Packer at al., 2002,Circulation, 106: 2194-2199).

However, despite the availability of various therapies, HF deaths havecontinued to rise steadily. This increase has been attributed to theaging of the population and the better survival of underlying diseases,such as for example myocardial infarction, resulting in more incidenceof HF as well as the availability of more treatment options which allowHF patients to live longer (American Heart Association, 2006, HeartDisease and Stroke Statistics, 2006 Update, Dallas, Tex.).

It is estimated that 35% to 60% of patients diagnosed with HF havenormal or near normal left ventricle ejection fraction (LVEF) (ACC/AHAGuideline, 2005, Circulation, 112:1825-1852). In HF patients withpreserved ejection fraction (HF-PEF), there is an impairment of cardiacrelaxation resulting in an abnormal ventricular filling (Adams et al.,2006, J Cardiac Fail, 12(1):10-38). Such patients differ from those withHF with reduced ejection fraction (HF-REF) in a number of importantways. Patients with HF-PEF tend to be older and female, and theirconditions are more likely to be associated with hypertension ratherthan with ischemia, and lower percentage of patients have priormyocardial infarction as compared to patients with reduced ejectionfraction (Bhatia et al., 2006, N Engl J Med, 355:260-290).

Pathophysiologic mechanisms that have been implicated in HF-PEF includeabnormal diastolic dysfunction with resultant increased ventricularfilling pressures, atrial enlargement, increased vascular stiffness, andabnormal systolic function despite relatively preserved ejectionfraction.

Left ventricular hypertrophy or concentric remodeling and left atrialenlargement are present in a majority of patients. In addition, leftatrial size and left ventricular mass are independently associated withan increased risk of morbidity and mortality. Therefore, the presence ofstructural remodeling is not only of diagnostic importance but alsoprovide important prognostic insights (Zile et al., 2011, Circulation,124(23):2491-501). As such a remodeled left atrium indicates increasedleft ventricular filling pressures that characterize heart failure butalso serves as substrate for atrial fibrillation. A treatment thataffects or even reduces the remodeling of the cardiac cavities isexpected to address the underlying pathophysiology and hence to preventdisease progression.

Atrial Fibrillation (AF) is the most common arrhythmia in patients withHeart Failure (HF); its prevalence increases with the severity of HF,and its occurrence is frequently associated with symptom deteriorationand increased morbidity.

Because the renin-angiotensin-aldosterone system (RAAS) is involved inmany of the processes associated with HF-PEF, inhibitors of RAS systemhave been of particular interest as a potential therapeutic interventionfor these patients. However, several recently completed large,prospective clinical trials (PEP-CHF, CHARM-Preserved, and I-PRESERVEtrials) have not demonstrated a significant benefit of blocking RAAS inimproving mortality and morbidity in this population (Cleland et al.,2006, Eur J Heart Failure, 8: 105-110; Yussef et al., 2003, Lancet,362:777-781; Massie et at, 2008, N Engl J Med., 359(23):2456-67), thoughthese agents have showed favorable effects in patients with a reducedEF.

As a result, to date, there is no proven pharmacologic therapy for theHF-PEF population. Consequently, many of the guidelines for heartfailure treatment do not address this group of patients (American HeartAssociation, 2006, Heart Disease and Stroke Statistics, 2006 Update,Dallas, Tex.; ESC Guidelines, 2008, Eur Heart J, 29:2388-2442). Rather,treatment options have been focused on treating co-morbidities, such ashypertension or diabetes. Just recently, in 2013, the American HeartAssociation has added to consider the administer Angiotensin ReceptorBlockers (ARBs) to decrease hospitalizations for patients with HF-PEF.

Therefore it would be highly advantageous to provide a new treatmentoption and indeed providing relief or at least improvement for HFpatients, and in particular for HF patients with preserved ejectionfraction (HF-PEF).

SUMMARY OF THE INVENTION

Surprisingly, the administration of a NEP (neutral endopeptidase,3.4.24.11) inhibitor or a pharmaceutically acceptable salt or esterthereof, or pro-drug thereof, in patients with heart failure withpreserved ejection fraction (HF-PEF), proved to reduce the left atrialvolume, the left atrial volume index (LAVI) and the left atrialdimension.

The present invention thus provides a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,for use in the treatment, prevention or delay of progression of adisease characterized and/or manifested by atrial enlargement and/orremodeling.

There is also provided a NEP inhibitor, or a pharmaceutically acceptablesalt or ester thereof, or pro-drug thereof, for use in the reduction ofthe left atrial volume, the left atrial volume index (LAVI) and/or theleft atrial dimension in patients suffering from a disease characterizedand/or manifested by atrial enlargement and/or remodeling.

Diseases characterized by atrial enlargement and/or remodeling include,but are not limited to heart failure with preserved ejection fraction(HF-PEF), heart failure with reduced ejection fraction (HF-REF), cardiacdysrhythmias comprising atrial fibrillation, new onset atrialfibrillation and recurrent atrial fibrillation; mitral stenosis andregurgitation, cardiomyopathies, hypertension or pulmonary heartdiseases.

In one embodiment, diseases characterized by atrial enlargement and/orremodeling include, but are not limited to, heart failure with preservedejection fraction (HF-PEF), cardiac dysrhythmias such as atrialfibrillation, new onset atrial fibrillation and recurrent atrialfibrillation, mitral regurgitation, cardiomegalies, cardiomyopathies orpulmonary heart diseases.

There is also provided a NEP inhibitor, or a pharmaceutically acceptablesalt or ester thereof, or pro-drug thereof, for use in the improvement,stabilization or delayed worsening in NYHA classification of patientssuffering from heart failure.

In one embodiment said patients suffering from heart failure arepatients suffering from heart failure with preserved ejection fraction(HF-PEF) or heart failure with reduced ejection fraction (HF-REF). Inone embodiment said patients suffering from heart failure are patientssuffering from heart failure with preserved ejection fraction (HF-PEF).

In another aspect of the invention, there is provided a pharmaceuticalcomposition, comprising a NEP inhibitor, or a pharmaceuticallyacceptable salt, or ester thereof, or pro-drug thereof, for use in thetreatment, prevention or delay of progression of a disease characterizedand/or manifested by atrial enlargement and/or remodeling.

In another aspect, there is also provided a method for treatment,prevention or delay of progression of a disease characterized and/ormanifested by atrial enlargement and/or remodeling comprisingadministration of a therapeutically effective amount, or aprophylactically effective amount, of a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereofto a subject, e.g. a human subject, in need of such treatment.

There is also provided a method for the reduction of the left atrialvolume, the left atrial volume index (LAVI) and/or the left atrialdimension in patients suffering from a disease characterized and/ormanifested by atrial enlargement and/or remodeling comprisingadministration of a therapeutically effective amount of a NEP inhibitor,or a pharmaceutically acceptable salt or ester thereof, or pro-drugthereof, to a subject, e.g. a human, in need of such treatment.

There is also provided a method for the improvement, stabilization ordelayed worsening in NYHA classification of patients suffering fromheart failure, comprising administration of a therapeutically effectiveamount of a NEP inhibitor, or a pharmaceutically acceptable salt orester thereof, or pro-drug thereof, to a subject, e.g. a human, in needof such treatment. In one embodiment said patients suffering from heartfailure are patients suffering from heart failure with preservedejection fraction (HF-PEF) or heart failure with reduced ejectionfraction (HF-REF). In one embodiment said patients suffering from heartfailure are patients suffering from heart failure with preservedejection fraction (HF-PEF).

In a further aspect, the present invention provides the use of a NEPinhibitor, or a pharmaceutically acceptable salt or ester thereof, orpro-drug thereof, for the manufacture of a medicament for the treatment,prevention or delay of progression of a disease characterized and/ormanifested by atrial enlargement and/or remodeling.

There is also provided the use of a NEP inhibitor, or a pharmaceuticallyacceptable salt or ester thereof, or pro-drug thereof, for themanufacture of a medicament for one or more of the following purposes:

(a) the reduction of the left atrial volume, the left atrial volumeindex (LAVI) and/or the left atrial dimension in patients suffering froma disease characterized and/or manifested by atrial enlargement and/orremodeling;

(b) the improvement, stabilization or delayed worsening in NYHAclassification of patients suffering from heart failure;

(c) the treatment or prevention of atrial fibrillation or for theprevention of or delay of the time to the new onset of atrialfibrillation in patients suffering from a disease characterized and/ormanifested by atrial enlargement and/or remodeling;

(d) the treatment of patients with no history of atrial fibrillation,wherein the NEP inhibitor pro-drug or NEP inhibitor delays the time tothe new onset of atrial fibrillation.

Diseases characterized by atrial enlargement and/or remodeling include,but are not limited to heart failure with preserved ejection fraction(HF-PEF), heart failure with reduced ejection fraction (HF-REF), cardiacdysrhythmias comprising atrial fibrillation, new onset atrialfibrillation and recurrent atrial fibrillation; mitral stenosis andregurgitation, cardiomyopathies, hypertension or pulmonary heartdiseases.

In one embodiment said patients suffering from heart failure arepatients suffering from heart failure with preserved ejection fraction(HF-PEF) or heart failure with reduced ejection fraction (HF-REF). Inone embodiment said patients suffering from heart failure are patientssuffering from heart failure with preserved ejection fraction (HF-PEF).

The NEP inhibitor pro-drug is preferablyN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester, or a pharmaceutically acceptable salt thereof, and theNEP inhibitor is preferablyN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or a pharmaceutically acceptable salt thereof.

In one aspect of the invention, the NEP inhibitor pro-drug or the NEPinhibitor is administered to patients already being treated with anAngiotensin Receptor Blocker, such as valsartan or a pharmaceuticallyacceptable salt thereof.

In another aspect of the invention, the NEP inhibitor pro-drug or theNEP inhibitor is administered together, concomitantly or sequentiallywith the Angiotensin Receptor Blocker valsartan or a pharmaceuticallyacceptable salt thereof.

This invention also provides that the NEP inhibitor pro-drug isadministered in the form of LCZ696, i.e. as trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the changes in NYHA and Clinical Composite assessment ofLCZ696 and valsartan treatment groups.

DETAILED DESCRIPTION OF THE INVENTION

Use of a NEP Inhibitor of NEP Inhibitor for Use

The present invention relates to a NEP inhibitor or a pharmaceuticallyacceptable salt or ester thereof, or pro-drug thereof, preferably theNEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, for use in thetreatment, prevention or delay of progression of a disease characterizedand/or manifested by atrial enlargement and/or remodeling.

The present invention also relates to a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, for use in thereduction of the left atrial volume, the left atrial volume index (LAVI)and/or the left atrial dimension in patients suffering from a diseasecharacterized and/or manifested by atrial enlargement and/or remodeling.

The present invention also relates to a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, for use in thetreatment, prevention or delay of progression of a disease characterizedand/or manifested by atrial enlargement and/or remodeling wherein thetreatment, prevention or delay of progression of a disease ischaracterized by the reduction of the left atrial volume, the leftatrial volume index (LAVI) and/or the left atrial dimension in patientssuffering from a disease characterized and/or manifested by atrialenlargement and/or remodeling.

Diseases characterized by atrial enlargement and/or remodeling include,but are not limited to heart failure with preserved ejection fraction(HF-PEF), heart failure with reduced ejection fraction (HF-REF), cardiacdysrhythmias comprising atrial fibrillation, new onset atrialfibrillation and recurrent atrial fibrillation; mitral stenosis andregurgitation, cardiomyopathies, hypertension or pulmonary heartdiseases.

In one embodiment, diseases characterized by atrial enlargement and/orremodeling include, but are not limited to, heart failure with preservedejection fraction (HF-PEF), cardiac dysrhythmias such as atrialfibrillation, new onset atrial fibrillation and recurrent atrialfibrillation, mitral regurgitation, cardiomegalies, cardiomyopathies orpulmonary heart diseases.

In one embodiment of the invention the disease characterized and/ormanifested by atrial enlargement and/or remodeling is heart failure withpreserved ejection fraction (HF-PEF).

In another embodiment of the invention the disease characterized and/ormanifested by atrial enlargement and/or remodeling is heart failure withreduced ejection fraction (HF-REF).

In one embodiment of the invention said patient is a warm-bloodedanimal.

In a further embodiment of the invention said warm-blooded animal is ahuman.

Furthermore, the present invention relates to a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, for use in theimprovement, stabilization or delayed worsening in NYHA classificationof patients suffering from heart failure.

In one embodiment patients suffering from heart failure are patientssuffering from heart failure with preserved ejection fraction (HF-PEF)or heart failure with reduced ejection fraction (HF-REF). In oneembodiment patients suffering from heart failure are patients sufferingfrom heart failure with preserved ejection fraction (HF-PEF).

The New York Heart Association (NYHA) classification grades the severityof heart failure symptoms as one of four functional classes. The NYHAclassification is widely used in clinical practice and in researchbecause it provides a standard description of severity that can be usedto assess response to treatment and to guide management.

The New York Heart Association functional classification based onseverity of symptoms and physical activity:

Class I: No limitation of physical activity. Ordinary physical activitydoes not cause undue breathlessness, fatigue, or palpitations.

Class II: Slight limitation of physical activity. Comfortable at rest,but ordinary physical activity results in undue breathlessness, fatigue,or palpitations.

Class III: Marked limitation of physical activity. Comfortable at rest,but less than ordinary physical activity results in unduebreathlessness, fatigue, or palpitations.

Class IV: Unable to carry on any physical activity without discomfort.Symptoms at rest can be present. If any physical activity is undertaken,discomfort is increased.

In one embodiment of the invention the NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for the treatmentor prevention of atrial fibrillation or for the prevention of or fordelaying the time until new onset of atrial fibrillation.

In a further embodiment, the NEP inhibitor, or a pharmaceuticallyacceptable salt or ester thereof, or pro-drug thereof, preferably theNEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for the treatmentor prevention of atrial fibrillation or for the prevention of or fordelaying the time until new onset of atrial fibrillation in patientssuffering from a disease characterized and/or manifested by atrialenlargement and/or remodeling.

In another embodiment, the NEP inhibitor, or a pharmaceuticallyacceptable salt or ester thereof, or pro-drug thereof, preferably theNEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for the treatmentor prevention of atrial fibrillation or for the prevention of or fordelaying the time until new onset of atrial fibrillation in patientssuffering from heart failure. In one embodiment patients suffering fromheart failure are patients suffering from heart failure with preservedejection fraction (HF-PEF) or heart failure with reduced ejectionfraction (HF-REF). In one embodiment patients suffering from heartfailure are patients suffering from heart failure with preservedejection fraction (HF-PEF).

In one embodiment of the invention the NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylrnethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for the treatmentof patients suffering from heart failure with preserved ejectionfraction (HF-PEF) with no history of atrial fibrillation.

In one embodiment of the invention the NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for the treatmentof patients suffering from heart failure with preserved ejectionfraction (HF-PEF) with no history of atrial fibrillation, wherein theNEP inhibitor pro-drug or NEP inhibitor prevents or delays the time tothe new onset of atrial fibrillation.

In one embodiment thereof, the NEP inhibitor, or a pharmaceuticallyacceptable salt or ester thereof, or pro-drug thereof, preferably theNEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is superior tovalsartan alone and/or enalapril alone in delaying the time to the newonset of atrial fibrillation.

In one embodiment of the invention, the NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for use ofreducing the level of plasma NT-proBNP in patients suffering from adisease characterized and/or manifested by atrial enlargement and/orremodeling, such as heart failure, in particular heart failure withpreserved ejection fraction.

In another embodiment of the invention, the NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, when administered orused in the context of the invention leads to a sustained reduction inplasma NT-proBNP concentration.

In the context of the present invention and all the aforementionedembodiments, the NEP inhibitor, or a pharmaceutically acceptable salt orester thereof, or pro-drug thereof, preferably the NEP inhibitorpro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, can in addition beused for the improvement, stabilization or delayed worsening in NYHAclassification of patients suffering from heart failure. In oneembodiment said patients suffering from heart failure are patientssuffering from heart failure with preserved ejection fraction (HF-PEF)or heart failure with reduced ejection fraction (HF-REF). In oneembodiment said patients suffering from heart failure are patientssuffering from heart failure with preserved ejection fraction (HF-PEF).

Definitions

Throughout this specification and in the claims that follow, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The term “prevention” refers to prophylactic administration to a healthysubject to prevent the development of the conditions mentioned herein.Moreover, the term “prevention” means prophylactic administration topatients being in a pre-stage of the conditions to be treated.

The term “delay of progression”, as used herein, refers toadministration to patients being in a pre-stage of the condition to betreated in which patients with a pre-form of the corresponding conditionis diagnosed.

The term “treatment” is understood the management and care of a patientfor the purpose of combating the disease, condition or disorder.

The term “therapeutically effective amount” refers to an amount of adrug or a therapeutic agent that will elicit the desired biologicaland/or medical response of a tissue, system or an animal (including man)that is being sought by a researcher or clinician.

The terms “warm-blooded animal or patient” include, but are not limitedto, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits and mice.The preferred mammals are humans.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or apharmaceutically acceptable salt or ester thereof, or a pro-drug thereofto a subject in need of treatment. The administration of the compositionof the present invention in order to practice the present methods oftherapy is carried out by administering a therapeutically effectiveamount of the compounds in the composition to a subject in need of suchtreatment or prophylaxis. The need for a prophylactic administrationaccording to the methods of the present invention is determined via theuse of well-known risk factors. The effective amount of an individualcompound is determined, in the final analysis, by the physician incharge of the case, but depends on factors such as the exact disease tobe treated, the severity of the disease and other diseases or conditionsfrom which the patient suffers, the chosen route of administration,other drugs and treatments which the patient may concomitantly require,and other factors in the physician's judgment.

The term “prophylactically effective amount” as used herein means theamount of the active compounds in the composition that will elicit thebiological or medical response in a tissue, system, subject, or humanthat is being sought by the researcher, veterinarian, medical doctor orother clinician, to prevent the onset of a disease characterized and/ormanifested by atrial enlargement and/or remodeling.

The term “pharmaceutically acceptable”, as used herein, refers to thosecompounds, materials, compositions and/or dosage forms, which are,within the scope of sound medical judgment, suitable for contact withthe tissues of mammals, especially humans, without excessive toxicity,irritation, allergic response and other problem complicationscommensurate with a reasonable benefit/risk ratio.

Neutral Endopeptidase

Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP;Biochem. J., 241, p. 237-247, 1987) is a zinc-containing metalbproteasethat cleaves a variety of peptide substrates on the amino terminal sideof aromatic amino acids. Substrates for this enzyme include, but are notlimited to, atrial natriuretic factors (ANF, also known as ANP), brainnatriuretic peptide (BNP), met and leu enkephalin, bradykinin,neurokinin A, and substance P.

ANPs are a family of vasodilator, diuretic and antihypertensive peptideswhich have been the subject of many reports in the literature, e.g.,Annu. Rev. Pharm. Tox., 29, 23-54, 1989. One form, ANF 99-126, is acirculating peptide hormone which is released from the heart duringconditions of cardiac distension. The function of ANF is to maintainsalt and water homeostasis as well as to regulate blood pressure. ANF israpidly inactivated in the circulation by at least two processes: by areceptor-mediated clearance as reported in Am. J. Physiol., 256,R469-R475, 1989, and by an enzymatic inactivation via NEP as describedin Biochem. J., 243, 183-187, 1987. It has been previously demonstratedthat inhibitors of NEP potentiate the hypotensive, diuretic, natriureticand plasma ANF responses to pharmacological injection of ANF inexperimental animals. The potentiation of ANF by two specific NEPinhibitors is reported by Sybertz et al. in J. Pharmacol. Exp. Ther 250,2, 624-631, 1989, and in Hypertension, 15, 2, 152-161, 1990, while thepotentiation of ANF by NEP—A—in general was disclosed in U.S. Pat. No.4,749,688. In U.S. Pat. No. 4,740,499 Olins disclosed the use ofthiorphan and kelatorphan to potentiate atrial peptides. Moreover, NEPinhibitors lower blood pressure and exert ANF-like effects such asdiuresis and increased cyclic guanosine 3′,5′-monophosphate (cGMP)excretion in some forms of experimental hypertension. Theantihypertensive action of NEP inhibitors is mediated through ANFbecause antibodies to ANF will neutralize the reduction in bloodpressure.

The in vitro inhibition of neutral endopeptidase (NEP) 3.4.24.11 can be,for example, determined as follows: Neutral endopeptidase 3.4.24.11activity can be determined by the hydrolysis of the substrateglutaryl-Ala-Ala-Phe-2-naphthylamide (GAAP) using a modified procedureof Orlowski and Wilk (1981). The incubation mixture (total volume 125μl) contains 4.2 μg of protein (rat kidney cortex membranes prepared bymethod of Maeda et al, 1983), 50 mM tris buffer, pH 7.4 at 25° C., 500μM substrate (final concentration), and leucine aminopeptidase M (2.5μg). The mixture is incubated for 10 minutes at 25° C. and 100 μl offast garnet (250 μg fast garnet/ml of 10% Tween 20 in 1M sodium acetate,pH 4.2) is added. Enzyme activity is measured spectrophotometrically at540 nm. One unit of NEP 24.11 activity is defined as 1 nmol of2-naphthylamine released per minute at 25° C. at pH 7.4. IC 50 valuesare determined, i.e. the concentration of test compound required for 50%inhibition of the release of 2-naphthylamine.

Neutral endopeptidase activity can be also determined using ANF as asubstrate. A trial natriuretic factor degrading activity is determinedby measuring the disappearance of rat-ANF (r-ANF) using a 3 minutereverse phase-HPLC separation. An aliquot of the enzyme in 50 mM TrisHCl buffer, pH 7.4, is preincubated at 37° C. for 2 minutes and thereaction is initiated by the addition of 4 nmol of r-ANF in a totalvolume of 50 μl. The reaction is terminated after 4 minutes with theaddition of 30 μl of 0.27% trifluoroacetic acid (TFA). Forty microlitersof the mixture is injected into a reverse phase-HPLC and analyzed usinga C4 cartridge in a 3 minute, isocratic separation. Twenty-three percentof buffer B (0.1% TFA in 80% acetonitrile) is used. Buffer A is 0.1% TFAin water. One unit of activity is defined as the hydrolysis of 1 nmol ofr-ANF per minute at 37° C. at pH 7.4. IC 50 values are determined, i.e.the concentration of test compound required for 50% inhibition of thehydrolysis of ANF.

The test compound can be dissolved, for example, in dimethyl sulfoxideor 0.25M sodium bicarbonate solution, and the solution is diluted withpH 7.4 buffer to the desired concentration.

NEP Inhibitor Pro-Drugs and NEP Inhibitors

The methods and compositions of the present invention comprise a NEPinhibitor, or a pharmaceutically acceptable salt or ester thereof orpro-drug thereof. The NEP inhibitor useful in the compositions of thepresent invention may be any NEP inhibitor known in the art.

A suitable NEP inhibitor which may be employed in the present inventionis, e.g., a compound of the formula (I)

whereinR₂ is C₁-C₇ alkyl, trifluoromethyl, optionally substituted phenyl or—(CH₂)₁₋₄-(optionally substituted phenyl);R₃ is hydrogen, C₁-C₇alkyl, optionally substituted phenyl,—(CH₂)₁₋₄-(optionally substituted phenyl);R₁ is hydroxy, C₁-C₇ alkoxy or NH₂;n is an integer from 1 to 15;or pharmaceutically acceptable salts thereof.

The term “optionally substituted phenyl” refers to a phenyl group whichmay optionally be substituted with a substituent selected from C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, hydroxy, Cl, Br, or F.

Preferred selective NEP inhibitors of formula (I) include compoundswherein:

R₂ is benzyl;

R₃ is hydrogen;

n is an integer from 1 to 9;

R₁ is hydroxy;

or pharmaceutically acceptable salts thereof.

Further preferred is a selective NEP inhibitor of formula (I) which isreported in the literature as SQ 28,603 wherein:

R₂ is benzyl;

R₃ is hydrogen;

n is one; and

R₁ is hydroxy.

The preparation of selective NEP inhibitors of formula (I) wherein R₂ isother than trifluoromethyl is disclosed by Delaney et al. in U.S. Pat.No. 4,722,810. The preparation of selective NEP inhibitors of formula(I) wherein R₂ is trifluoromethyl is disclosed by Delaney et al. in U.S.Pat. No. 5,223,516.

Further NEP inhibitors within the scope of the present invention includecompounds disclosed in U.S. Pat. No. 4,610,816, herein incorporated byreference, including in particular N—[N-[1(S)-carboxyl-3-phenylproplyl]-(S)-phenylalanyl]-(S)-isoserine andN—[N-[((1S)-carboxy-2-phenyl)ethyl]-(S)-phenylalanyl]-β-alanine;compounds disclosed in U.S. Pat. No. 4,929,641, in particularN-[2(S)-mercaptomethyl-3-(2-methylphenyl)-propionyl]-methionine; SQ28,603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-β-alanine),disclosed in South African Patent Application 84/0670; UK 69578(cis-4-[[[1-[2-carboxy-3-(2-methoxyethoxy)-propyl]-cyclopentyl]carbonyl]amino]-cyclohexanecarboxylicacid) and its active enantiomer(s); thiorphan and its enantiomers;retro-thiorphan; phosphoramidon; and SQ 29,072(7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]-heptanoic acid).

NEP inhibitors within the scope of the present invention also includethe compounds disclosed in U.S. Pat. No. 5,217,996, particularly,N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester andN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or in each case, a pharmaceutically acceptable salt thereof; thecompounds disclosed in EP 00342850, particularly(S)-cis-4-[1-[2-(5-indanyloxycarbonyl)-3-(2-methoxyethoxy)propyl]-1-cyclopentanecarboxamido]-1-cyclohexanecarboxylicacid; the compounds disclosed in GB 02218983, particularly3-(1-[6-endo-hydroxymethylbicyclo[2,2,1]heptane-2-exo-carbamoyl]-cyclopentyl)-2-(2-methoxyethyl)propanoicacid; the compounds disclosed in WO 92/14706, particularlyN-(1-(3-(N-t-butoxycarbonyl-(S)-prolylamino)-2(S)-t-butoxy-carbonylpropyl)-cyclopentanecarbonyl)-O-benzyl-(S)-serinemethyl ester; the compounds disclosed in EP 00343911; the compoundsdisclosed in JP 06234754; the compounds disclosed in EP 00361365,particularly 4-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]benzoicacid; the compounds disclosed in WO 90/09374, particularly3-[1-(cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1-carboamoyl)cyclopentyl]-2S-(2-methoxyethoxymethyl)propanoicacid; the compounds disclosed in JP 07157459, particularlyN-((2S)-2-(4-biphenylmethyl)-4-carboxy-5-phenoxyvaleryl)glycine; thecompounds disclosed in WO 94/15908 particularlyN-(1-(N-hydroxycarbamoylmethyl)-1-cydopentanecarbonyl)-L-phenylalanine;the compounds disclosed in U.S. Pat. No. 5,273,990 particularly(S)-(2-biphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylamino) methylphosphonicacid; the compounds disclosed in U.S. Pat. No. 5,294,632 particularly(S)-5-(N-(2-(phosphonomethylamino)-3-(4-biphenyl)propionyl)-2-aminoethyl)tetrazole;the compounds disclosed in U.S. Pat. No. 5,250,522, particularlyβ-alanine,3-[1,1′-biphenyl]-4-yl-N-[diphenoxyphosphinyl)methyl]-L-alanyl; thecompounds disclosed in EP 00636621, particularlyN-(2-carboxy-4-thienyl)-3-mercapto-2-benzylpropanamide; the compoundsdisclosed in WO 93/09101, particularly2-(2-mercaptomethyl-3-phenylpropionamido)thiazol-4-ylcarboxylic acid;the compounds disclosed in EP 00590442 particularly((L)-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy)carbonyl)-2-phenylethyl)-L-phenylalanyl)-β-alanine,N—[N-[(L)-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-(R)-alanine,N—[N-[(L)-1-carboxy-2-phenylethyl]-L-phenylalanyl]-(R)-alanine,N-[2-acetylthiomethyl-3-(2-methyl-phenyl)-propionyl]-methionine ethylester, N-[2-mercaptomethyl-3-(2-methylphenyl)propioyl]-methionine,N-[2(S)-mercaptomethyl-3-(2-methylphenyl)propanoyl]-(S)-isoserine,N—(S)-[3-mercapto-2-(2-methylphenyl)propionyl]-(S)-2-methoxy-(R)-alanine,N-[1-[[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino]cyclopentylcarbonyl]-(S)-isoserine,N-[1-[[1(S)-carbonyl-3-phenylpropy]amino]-cyclopentylcarbonyl]-(S)-isoserine,1,1′-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propanediyl]]-bis-(S)-isoserine,1,1′-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propanediyl]]-bis-(S)-methionine,N-(3-phenyl-2-(mercaptomethyl)-propionyl)-(S)-4-(methylmercapto)methionine,N-[2-acetylthiomethyl-3-phenyl-propionyl]-3-aminobenzoic acid,N-[2-mercaptomethyl-3-phenyl-propionyl]-3-aminobenzoic acid,N-[1-(2-carboxy-4-phenylbutyl)-cyclopentanecarbonyl]-(S)-isoserine,N-[1-(acethylthiomethyl)-cyclopentane-carbonyl]-(S)-methionine ethylester,3(S)-[2-(acetylthiomethyl)-3-phenyl-propionyl]amino-e-caprolactam; andthe compounds disclosed in WO 93/10773, particularly,N-(2-acetylthiomethyl-3-(2-methylphenyl)propionyl)-methionine ethylester.

Also suitable for use are any pro-drug forms of the above-listed NEPinhibitors, e.g., compounds in which one or more carboxylic acid groupsare esterified.

Especially suitable NEP inhibitors includeN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester andN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid of the formulae

respectively, or in each case, a pharmaceutically acceptable saltthereof.

Preferred salts of the compound of formula (II) include, but are notlimited to, a sodium salt disclosed in U.S. Pat. No. 5,217,996; and atriethanolamine or a tris(hydroxymethyl)aminomethane salt disclosed inWO 03/059345.

The subject matter relating to NEP inhibitors referred herein above,e.g., in U.S. patents and EP, GB, JP or WO patent applications, isherewith incorporated by reference, especially the subject mattercorresponding to NEP inhibitors, and pharmaceutically acceptable saltsand the preparation of the NEP inhibitors and pharmaceuticalcompositions thereof, that are disclosed herein.

Pro-drug derivatives of any compound of the invention are derivatives ofsaid compounds which following administration release the parentcompound in vivo via some chemical or physiological process, e.g., apro-drug on being brought to the physiological pH or through enzymeaction is converted to the parent compound. Exemplary pro-drugderivatives are, e.g., esters of free carboxylic acids and S-acyl andO-acyl derivatives of thiols, alcohols or phenols. Preferred arepharmaceutically acceptable ester derivatives convertible by solvolysisunder physiological conditions to the parent carboxylic acid, e.g.,lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzylesters, mono- or di-substituted lower alkyl esters, such as theomega-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the alpha-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart.

In view of the close relationship between the free compounds, thepro-drug derivatives and the compounds in the form of their salts,whenever a compound is referred to in this context, a pro-drugderivative and a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

In any of the aspects mentioned throughout this specification, the term“a NEP inhibitor” or “the NEP inhibitor” preferably refers toN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid or a pharmaceutically acceptable salt thereof; and the term “a NEPinhibitor pro-drug” or “the NEP inhibitor pro-drug” preferably refers toN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or a pharmaceutically acceptable salt thereof.

With regard to the especially suitable NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester and the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, and pharmaceutically acceptable salts thereof, in the context ofthe present invention, these can be used either alone or for patientswhich are already been treated with an Angiotensin Receptor Blocker.

The Angiotensin Receptor Blocker can be any known in the art, such asvalsartan, irbesartan, losartan, olmesartan, eprosartan, telmisartan,azilsartan or a pharmaceutical acceptable salt thereof. Preferably, theNEP inhibitor pro-drug or NEP inhibitor is used in patients alreadytreated with valsartan or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, and for all of its uses, the NEPinhibitor pro-drug or NEP inhibitor is administered together,concomitantly or sequentially with the Angiotensin Receptor Blockervalsartan or a pharmaceutically acceptable salt thereof. Preferably theNEP inhibitor pro-drug or the NEP inhibitor and the Angiotensin ReceptorBlocker valsartan are administered in a 1:1 molar ratio.

In one embodiment of the invention, the NEP inhibitor pro-drug and theangiotensin receptor blocker are delivered together by administration oftrisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate(LCZ696). LCZ696 and formulations containing it are described anddisclosed in international patent applications WO 2001/056546 and WO2009/061713, which are herewith incorporated by reference.

Pharmaceutical Compositions

In another aspect the present invention also provides pharmaceuticalcompositions comprising a NEP inhibitor as defined herein above or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, and one or morepharmaceutically acceptable carrier or excipient, for use in thetreatment, prevention or delay of progression of a disease characterizedand/or manifested by atrial enlargement and/or remodeling.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising a NEP inhibitor, or a pharmaceuticallyacceptable salt or ester thereof, or pro-drug thereof, preferably theNEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, and one or morepharmaceutically acceptable carrier or excipient, for use in thereduction of the left atrial volume, the left atrial volume index (LAVI)and/or the left atrial dimension in patients suffering from a diseasecharacterized and/or manifested by atrial enlargement and/or remodeling.

Diseases characterized by atrial enlargement and/or remodeling include,but are not limited to heart failure with preserved ejection fraction(HF-PEF), heart failure with reduced ejection fraction (HF-REF), cardiacdysrhythmias comprising atrial fibrillation, new onset atrialfibrillation and recurrent atrial fibrillation; mitral stenosis andregurgitation, cardiomyopathies, hypertension or pulmonary heartdiseases.

In one embodiment, diseases characterized by atrial enlargement and/orremodeling include, but are not limited to, heart failure with preservedejection fraction (HF-PEF), cardiac dysrhythmias such as atrialfibrillation, new onset atrial fibrillation and recurrent atrialfibrillation, mitral regurgitation, cardiomegalies, cardiomyopathies orpulmonary heart diseases.

In one embodiment of the invention the disease characterized by atrialenlargement and remodeling is heart failure with preserved ejectionfraction (HF-PEF).

The invention also relates to pharmaceutical compositions comprising aNEP inhibitor, or a pharmaceutically acceptable salt or ester thereof,or pro-drug thereof, preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, and one or morepharmaceutically acceptable carrier or excipient, for use in theimprovement, stabilization or delayed worsening in NYHA classificationof patients suffering from heart failure.

In one embodiment patients suffering from heart failure are patientssuffering from heart failure with preserved ejection fraction (HF-PEF)or heart failure with reduced ejection fraction (HF-REF). In oneembodiment patients suffering from heart failure are patients sufferingfrom heart failure with preserved ejection fraction (HF-PEF).

In one embodiment, the invention also relates to a pharmaceuticalcomposition comprising a NEP inhibitor, or a pharmaceutically acceptablesalt or ester thereof, or pro-drug thereof, preferably the NEP inhibitorpro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, wherein thecomposition is for the treatment or prevention of atrial fibrillation orfor the prevention of or for delaying the time until new onset of atrialfibrillation.

In a further embodiment, the pharmaceutical composition comprising a NEPinhibitor, or a pharmaceutically acceptable salt or ester thereof, orpro-drug thereof, preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, wherein thecomposition is for the treatment or prevention of atrial fibrillation orfor the prevention of or for delaying the time until new onset of atrialfibrillation in patients suffering from a disease characterized and/ormanifested by atrial enlargement and/or remodeling.

In another embodiment, the pharmaceutical composition comprising the NEPinhibitor, or a pharmaceutically acceptable salt or ester thereof, orpro-drug thereof, preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for the treatmentor prevention of atrial fibrillation or for the prevention of or fordelaying the time until new onset of atrial fibrillation in patientssuffering from heart failure. In one embodiment patients suffering fromheart failure are patients suffering from heart failure with preservedejection fraction (HF-PEF) or heart failure with reduced ejectionfraction (HF-REF). In one embodiment patients suffering from heartfailure are patients suffering from heart failure with preservedejection fraction (HF-PEF).

In one embodiment of the invention, the pharmaceutical compositioncomprising the NEP inhibitor, or a pharmaceutically acceptable salt orester thereof, or pro-drug thereof, preferably the NEP inhibitorpro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for the treatmentof patients suffering from heart failure with preserved ejectionfraction (HF-PEF) with no history of atrial fibrillation.

In one embodiment of the invention, the pharmaceutical compositioncomprising the NEP inhibitor, or a pharmaceutically acceptable salt orester thereof, or pro-drug thereof, preferably the NEP inhibitorpro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylrnethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for the treatmentof patients suffering from heart failure with preserved ejectionfraction (HF-PEF) with no history of atrial fibrillation, wherein theNEP inhibitor pro-drug or NEP inhibitor prevents or delays the time tothe new onset of atrial fibrillation.

In one embodiment thereof, the pharmaceutical composition comprising theNEP inhibitor, or a pharmaceutically acceptable salt or ester thereof,or pro-drug thereof, preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is superior tovalsartan alone and/or enalapril alone in delaying the time to the newonset of atrial fibrillation.

In one embodiment of the invention, the pharmaceutical compositioncomprising the NEP inhibitor, or a pharmaceutically acceptable salt orester thereof, or pro-drug thereof, preferably the NEP inhibitorpro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is for reducing thelevel of plasma NT-proBNP in patients suffering from a diseasecharacterized and/or manifested by atrial enlargement and/or remodeling,such as heart failure, in particular heart failure with preservedejection fraction.

In another embodiment of the invention, the pharmaceutical compositioncomprising the NEP inhibitor, or a pharmaceutically acceptable salt orester thereof, or pro-drug thereof, preferably the NEP inhibitorpro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, when administered orused in the context of the invention leads to a sustained reduction inplasma NT-proBNP concentration.

In the context of the present invention and all the aforementionedembodiments, the pharmaceutical composition comprising the NEPinhibitor, or a pharmaceutically acceptable salt or ester thereof, orpro-drug thereof, preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, can in addition beused for the improvement, stabilization or delayed worsening in NYHAclassification of patients suffering from heart failure.

In one embodiment said patients suffering from heart failure arepatients suffering from heart failure with preserved ejection fraction(HF-PEF) or heart failure with reduced ejection fraction (HF-REF). Inone embodiment said patients suffering from heart failure are patientssuffering from heart failure with preserved ejection fraction (HF-PEF).

The pharmaceutical compositions for use according to the presentinvention comprise a therapeutically effective amount of a NEP inhibitoras defined herein above or a pharmaceutically acceptable salt or esterthereof, or pro-drug thereof. Each dosage unit can contain the dailydose or may contain a fraction of the daily dose, such as one-half orone-third of the dose.

In one embodiment, the pharmaceutical composition comprises the NEPinhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof.

In one embodiment, the pharmaceutical composition of the presentinvention can be used for patients which are already been treated withan Angiotensin Receptor Blocker as set out above.

In one embodiment of the invention for all of its uses, thepharmaceutical composition comprises the the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, and the AngiotensinReceptor Blocker valsartan or a pharmaceutically acceptable saltthereof. Such combinations are for example disclosed withininternational patent application WO 2003/059345, which is herewithincorporated by reference.

In one embodiment, the pharmaceutical composition comprises the NEPinhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, and the AngiotensinReceptor Blocker valsartan or a pharmaceutically acceptable saltthereof, in a 1:1 molar ratio.

In a further embodiment of the invention, the pharmaceuticalcompositions for use according to the present invention deliver the NEPinhibitor pro-drug and the angiotensin receptor blocker together to thepatient upon administration by comprising trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate(LCZ696). LCZ696 and formulations comprising it are described anddisclosed in international patent applications WO 2007/056546 and WO2009/061713.

The pharmaceutical compositions according to the invention can beprepared in a manner known per se and are those suitable for enteral,such as oral or rectal, and parenteral administration to mammals(warm-blooded animals), including man, comprising a therapeuticallyeffective amount of the pharmacologically active compound, alone or incombination with one or more pharmaceutically acceptable carriers,especially suitable for enteral or parenteral application.

The pharmaceutical preparations of the invention contain, for example,from about 0.1% to about 100%, e.g. 80% or 90%, or from about 1% toabout 60%, of the active ingredient. The term “about” or“approximately”, as used herein in each instance, shall have the meaningof within 10%, more preferably within 5%, of a given value or range.

Pharmaceutical preparations according to the invention for enteral orparenteral administration are, e.g., those in unit dose forms, such assugar-coated tablets, tablets, capsules, bars, sachets, granules,syrups, aqueous or oily suspensions or suppositories and furthermoreampoules. These are prepared in a manner known per se, e.g. by means ofconventional mixing, granulating, sugar-coating, dissolving orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active ingredient with solid carriers,if desired granulating a mixture obtained, and processing the mixture orgranules, if desired or necessary, after addition of suitable excipientsto give tablets or sugar-coated tablet cores.

Tablets may be formed from the active compound with fillers, for examplecalcium phosphate; disintegrating agents, for example maize starch,lubricating agents, for example magnesium stearate; binders, for examplemicrocrystalline cellulose or polyvinylpyrrolidone and other optionalingredients known in the art to permit tabletting the mixture by knownmethods. Similarly, capsules, for example hard or soft gelatin capsules,containing the active compound with or without added excipients, may beprepared by known methods. The contents of the capsule may be formulatedusing known methods so as to give sustained release of the activecompound.

Other dosage forms for oral administration include, for example, aqueoussuspensions containing the active compound in an aqueous medium in thepresence of a non-toxic suspending agent such as sodiumcarboxymethylcellulose, and oily suspensions containing the activecompounds in a suitable vegetable oil, for example arachis oil.

The active compound may be formulated into granules with or withoutadditional excipients. The granules may be ingested directly by thepatient or they may be added to a suitable liquid carrier (e.g. water)before ingestion. The granules may contain disintegrants, e.g. aneffervescent pair formed from an acid and a carbonate or bicarbonatesalt to facilitate dispersion in the liquid medium.

The dosage of the active ingredient of the composition will, of course,vary with the nature of the severity of the condition to be treated andwith the particular compound in the composition and its route ofadministration. It will also vary according to the age, weight andresponse of the individual patient.

Furthermore, the invention relates to a commercial package comprising aNEP inhibitor, or a pharmaceutically acceptable salt or ester thereof,or pro-drug thereof, preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereto and a package insertor other labeling including directions for treating a diseasecharacterized and/or manifested by atrial enlargement and/or remodelingby administering a NEP inhibitor, or a pharmaceutically acceptable saltor ester thereof, or pro-drug thereof, to a patient in need thereof.

In a preferred embodiment, the package insert or other labelingincluding directions for treating a disease characterized and/ormanifested by atrial enlargement and/or remodeling by administering atherapeutically effective amount of a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to a patient in needthereof.

In general, the daily dose range of the NEP inhibitor or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, lies within therange of from about 0.01 mg/kg to about 100 mg/kg, preferably from about0.1 mg/kg to about 50 mg/kg body weight of a subject in single ordivided doses. In one embodiment, the daily dose range of the NEPinhibitor is from about 0.1 mg/kg to about 25 mg/kg, or from about 1mg/kg to about 25 mg/kg body weight of a subject in single or divideddoses. On the other hand, it may be necessary to use dosages outsidethese limits in some cases.

In the case where an oral composition is employed, a suitable dosagerange of the NEP inhibitor or a pharmaceutically acceptable salt orester thereof, or pro-drug thereof, preferably the NEP inhibitorpro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is, e.g. from about0.01 mg/kg to about 100 mg/kg in the composition per day, preferablyfrom about 0.01 mg to about 2000 mg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining from about 0.01 mg to about 2,000 mg, e.g. about 0.01, about0.05, about 0.1, about 0.2, about 0.5, about 1.0, about 2.5, about 5,about 10, about 15, about 20, about 25, about 30, about 40, about 50,about 75, about 100, about 125, about 150, about 175, about 200, about225, about 250, about 500, about 750, about 850, about 1000 or about2000 milligrams of the active ingredient. This dosage regimen may beadjusted to provide the optimal therapeutic response. For example, theNEP-inhibitor may be administered once daily over a period of severaldays, several (1, 2, 3, 4, or more) weeks or even longer. In anotherembodiment, the NEP-inhibitor is administered once, or several (e.g. 1,2, 3) times daily.

Preferably, said tablets contain from about 10 mg to about 1000 mg, morepreferably from about 10 mg to about 500 mg, most preferably from about20 mg to about 250 mg, such as for example about 10 mg, about 15 mg,about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200mg, about 225 mg, about 250 mg of the active ingredient, which ispreferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof.

In one embodiment the NEP inhibitor or a pharmaceutically acceptablesalt or ester thereof, or pro-drug thereof, is administered twice daily.

In another embodiment the tablet contains 100 mg of the NEP inhibitor ora pharmaceutically acceptable salt or ester thereof, or pro-drugthereof, preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, and is administeredtwice daily.

In one embodiment, when the NEP inhibitor or a pharmaceuticallyacceptable salt or ester thereof, or pro-drug thereof, preferably theNEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, is co-administeredwith the angiotensin receptor blacker valsartan or a pharmaceuticallyacceptable salt thereof, the dose of the angiotension receptor blockervalsartan is as follows: Valsartan is preferably used in the form of anoral composition, preferably provided in the form of tablets (e.g. inthe form of the approved drug known under the trademark DIOVAN®),containing from about 0.01 mg to about 2000 mg, e.g. about 0.01, about0.05, about 0.1, about 0.2, about 0.5, about 1.0, about 2.5, about 5,about 10, about 15, about 20, about 25, about 30, about 40, about 50,about 75, about 100, about 125, about 150, about 175, about 200, about225, about 250, about 500, about 750, about 850, about 1000 or about2000 milligrams of the active ingredient.

Preferably, said valsartan tablets contain from about 10 mg to about1000 mg, more preferably from about 10 mg to about 500 mg, mostpreferably from about 20 mg to about 250 mg, such as for example about10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg,about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg,about 175 mg, about 200 mg, about 225 mg, about 250 mg of the activeingredient. In a particular embodiment, such valsartan tablets comprise80 mg, 160 mg, 320 mg or 640 mg of active ingredient.

In the embodiments where the NEP inhibitor pro-drug is provided in theform of LCZ696 as trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydratein the pharmaceutical compositions for use in the context of the presentinvention, the unit dose of the therapeutic agentsN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester and valsartan together will be in the range from about1 to about 1000 mg, such as 40 mg to 400 mg (e.g., 50 mg, 100 mg, 200mg, 400 mg) per day. Alternatively lower doses may be given, for exampledoses of 0.5 to 100 mg; 0.5 to 50 mg; or 0.5 to 20 mg per day. (Asexplanatory note, a unit dose of 100 mg LCZ696 delivering 100 mg of thetwo agentsN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenymethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester and valsartan corresponds to 107.8 mg of trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate.Correspondingly, a unit dose of 200 mg requires 215.6 mg, and a unitdose of 400 mg requires 431.2 mg of trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate.

Method of Treatment

The present invention also relates to a method for treatment, theprevention or delay of progression of a disease characterized and/ormanifested by atrial enlargement and/or remodeling comprisingadministration of a therapeutically effective amount, or aprophylactically effective amount, of a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to a subject, e.g. ahuman subject, in need of such treatment.

The present invention also relates to a method for the reduction of theleft atrial volume, the left atrial volume index (LAVI) and/or the leftatrial dimension in patients suffering from a disease characterized andfor manifested by atrial enlargement and/or remodeling comprisingadministration of a therapeutically effective amount of a NEP inhibitor,or a pharmaceutically acceptable salt or ester thereof, or pro-drugthereof, preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to a subject, e.g. ahuman, in need of such treatment.

Diseases characterized by atrial enlargement and/or remodeling include,but are not limited to heart failure with preserved ejection fraction(HF-PEF), heart failure with reduced ejection fraction (HF-REF), cardiacdysrhythmias comprising atrial fibrillation, new onset atrialfibrillation and recurrent atrial fibrillation; mitral stenosis andregurgitation, cardiomyopathies, hypertension or pulmonary heartdiseases.

In one embodiment, diseases characterized by atrial enlargement and/orremodeling include, but are not limited to, heart failure with preservedejection fraction (HF-PEF), cardiac dysrhythmias such as atrialfibrillation, new onset atrial fibrillation and recurrent atrialfibrillation, mitral regurgitation, cardiomegalies, cardiomyopathies orpulmonary heart diseases.

In one embodiment said disease characterized and/or manifested by atrialenlargement and/or remodeling is heart failure with preserved ejectionfraction (HF-PEF).

Furthermore, the present invention relates to a method for theimprovement, stabilization or delayed worsening in NYHA classificationof patients suffering from heart failure, comprising administration of atherapeutically effective amount of a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to a subject, e.g. ahuman, in need of such treatment.

In one embodiment patients suffering from heart failure are patientssuffering from heart failure with preserved ejection fraction (HF-PEF)or heart failure with reduced ejection fraction (HF-REF). In oneembodiment patients suffering from heart failure are patients sufferingfrom heart failure with preserved ejection fraction (HF-PEF).

The present invention also relates to a method for the treatment orprevention of atrial fibrillation or for the prevention of or fordelaying the time until new onset of atrial fibrillation comprisingadministration of a therapeutically effective amount, or aprophylactically effective amount, of a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to a subject, e.g. ahuman subject, in need of such treatment.

In a further embodiment, the present invention relates to a method forthe treatment or prevention of atrial fibrillation or far the preventionof or for delaying the time until new onset of atrial fibrillationcomprising administration of a therapeutically effective amount, or aprophylactically effective amount, of a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to a patientsuffering from a disease characterized and/or manifested by atrialenlargement and/or remodeling.

In another embodiment, the present invention relates to a method for thetreatment or prevention of atrial fibrillation or for the prevention ofor for delaying the time until new onset of atrial fibrillationcomprising administration of a therapeutically effective amount, or aprophylactically effective amount, of a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to a patientsuffering from heart failure. In one embodiment patients suffering fromheart failure are patients suffering from heart failure with preservedejection fraction (HF-PEF) or heart failure with reduced ejectionfraction (HF-REF). In one embodiment patients suffering from heartfailure are patients suffering from heart failure with preservedejection fraction (HF-PEF).

In one embodiment of the invention the method comprises administrationof a therapeutically effective amount, or a prophylactically effectiveamount, of a NEP inhibitor, or a pharmaceutically acceptable salt orester thereof, or pro-drug thereof, preferably the NEP inhibitorpro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to a patientsuffering from heart failure with preserved ejection fraction (HF-PEF)with no history of atrial fibrillation.

In one embodiment, the invention relates to a method for treatmentcomprising administration of a therapeutically effective amount, or aprophylactically effective amount, of a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to patientssuffering from heart failure with preserved ejection fraction (HF-PEF)with no history of atrial fibrillation, wherein the NEP inhibitorpro-drug or NEP inhibitor prevents or delays the time to the new onsetof atrial fibrillation.

In one embodiment thereof, the administration of the NEP inhibitorpro-drug or NEP inhibitor is superior to valsartan alone and/orenalapril alone in delaying the time to the new onset of atrialfibrillation.

In one embodiment, the present invention relates to a method forreducing the level of plasma NT-proBNP in patients comprisingadministration of a therapeutically effective amount, or aprophylactically effective amount, of a NEP inhibitor, or apharmaceutically acceptable salt or ester thereof, or pro-drug thereof,preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to said patientsuffering from a disease characterized and/or manifested by atrialenlargement and/or remodeling, such as heart failure, in particularheart failure with preserved ejection fraction.

In another embodiment of the invention, the NEP inhibitor pro-drug orNEP inhibitor—when administered or used in the context of theinvention—leads to a sustained reduction in plasma NT-proBNPconcentration.

In the context of the present invention and all the aforementionedembodiments, the method comprising administration of a therapeuticallyeffective amount, or a prophylactically effective amount, of a NEPinhibitor, or a pharmaceutically acceptable salt or ester thereof, orpro-drug thereof, preferably the NEP inhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester or the NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or pharmaceutically acceptable salts thereof, to a patient in needthereof, is in addition used for the improvement, stabilization ordelayed worsening in NYHA classification of patients suffering fromheart failure.

In one embodiment said patients suffering from heart failure arepatients suffering from heart failure with preserved ejection fraction(HF-PEF) or heart failure with reduced ejection fraction (HF-REF). Inone embodiment said patients suffering from heart failure are patientssuffering from heart failure with preserved ejection fraction (HF-PEF).

The following example is illustrative, but does not serve to limit thescope of the invention described herein.

Example 1

A 36-week, randomized, double-blind, multi-center, parallel group,active controlled study to evaluate the efficacy, safety, andtolerability of LCZ696 compared to valsartan in patients with chronicheart failure with preserved left-ventricular ejection fraction(HF-PEF).

LCZ696:

LCZ696 refers to the supramolecular complex trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate.This compound and pharmaceutical compositions thereof have beenpreviously disclosed in WO2007/056546 and WO 2009/061713, whosepreparative teachings are incorporated herein by reference.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitorthat comprises the molecular moieties of the NEP (neutral endopeptidaseEC 3.4.24.11) inhibitor pro-drug AHU377(N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester) and the angiotensin receptor blocker valsartan as asingle compound. AHU377 is metabolized by enzymatic cleavage to LBQ657(N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid), the active inhibitor of neutral endopeptidase, which is the majorenzyme responsible for the breakdown of atrial natriuretic peptides.

Valsartan:

Valsartan or(S)—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}valine)can be purchased from commercial sources or can be prepared according toknown methods, such as described in U.S. Pat. No. 5,399,578 and EP0443983, whose preparative teachings are incorporated by referenceherein.

Study Design:

Men and women aged 40 years or older with a left ventricular ejectionfraction of 45% or above, and a documented history of heart failure withassociated signs or symptoms (dyspnea on exertion, orthopnea, paroxysmaldyspnea, and peripheral edema) are eligible. Patients are required tohave an NT-proBNP>400 pg/mL at screening, be on diuretic therapy, andhave a systolic blood pressure less than 140 mm Hg, or 160 mm Hg or lessif on three or more blood pressure medications at randomization.Additional inclusion criteria include an estimated glomerular filtrationrate (eGFR) of at least 30 ml/min/1.73 m² at screening (calculated bythe Modification of Diet in Renal Disease formula) and a potassium of nomore than 5.2 mmol/L.

Patients are excluded if they had prior left ventricular ejectionfraction less than 45% at any time, isolated right heart failure due topulmonary disease, dyspnea due to non-cardiac causes such as pulmonarydisease, anemia, or severe obesity, primary valvular or myocardialdiseases, or coronary artery or cerebrovascular disease requiringrevascularization within 3 months of screening or likely to requirerevascularization during the trial.

Eligible patients are enrolled into a 2-week, single-blind placeborun-in period, during which time they continue their backgroundmedications. ACE inhibitors and angiotensin receptor blockers arerequired to be discontinued 24 hours prior to randomization. After twoweeks, all patients who fulfill the inclusion/exclusion criteria arerandomized to either LCZ696 or valsartan in a 1:1 ratio.

Patients are started on LCZ696 50 mg twice daily or valsartan 40 mgtwice daily and are titrated to their final medication doses of LCZ696200 mg twice daily or valsartan 160 mg twice daily over a period of 2 to4 weeks. Patients are on their starting dose for 1 week and titrated upto either LCZ696 100 mg twice daily or valsartan 80 mg twice daily for 1week. The maximum LCZ696 dose achieves exposures similar to a dose ofvalsartan that provides comparable ATI blockade. At the investigatorsdiscretion, patients are allowed to stay on each titration dose for anadditional week. All patients are then titrated to their final doses ofLCZ696 200 mg twice daily or valsartan 160 mg twice daily, in additionto standard background therapy. Patients remain on these doses for theremainder of the study, although those not tolerating the maximum doseof study medication could be down-titrated to a lower dose at theInvestigators discretion and then re-challenged to the maximum dose ofstudy medication, or remain on the lower dose.

The dose selection reflects equal exposure of valsartan in both studyarms as published by Gu et al., 2010, J Clin Pharmacol., 401-14 andRuilope et al., 2010, Lancet, 375(9722):1255-66.

Study Procedures:

The primary study endpoint is the change from baseline in NT-proBNPassessed at 12 weeks, and is analyzed using the last observation afterbaseline carried forward. Secondary endpoints include changes inechocardiographic measures (left ventricular volumes and ejectionfraction, left atrial volume, measures of diastolic function), change inblood pressure, as well as change in New York Heart Association Class(NYHA) clinical composite assessment and quality of life (Kansas CityCardiomyopathy Questionnaire). Echocardiographic studies are performedat screening, randomization, at week 12, and week 36 or at end of studyor early termination visits. Echocardiograms performed at screening areevaluated by local readers for qualifying information. All otherechocardiograms are only performed in patients meeting NT-proBNP entrycriterion and are evaluated centrally. For assessment of globalventricular size and function, left ventricular end-diastolic andend-systolic volumes are obtained utilizing the Simpson's rule methodand left ventricular ejection fraction is derived in the usual fashion.Maximal left atrial dimension is measured in the parasternal long-axisview, and left atrial volume is assessed with the Simpson's rule methodand indexed to body surface area. Measurements are made in triplicate inaccordance with the recommendations of the American Society ofEchocardiography. Blood pressure and heart rate are measured at allstudy visits with a calibrated standard sphygmomanometer and appropriatesize cuff. The use of concomitant medication is recorded at each studyvisit.

The clinical composite assessment is based on a composite of the NYHAfunctional classification, patient global assessment and major adverseclinical events. Patients are classified as improved if at the endpointvisit they experienced improvement in NYHA functional classification orin patient global assessment (or both) but do not have a major adversecardiovascular event. Patients are determined to be worse if at theendpoint visit they experienced a major adverse cardiac event during thedouble blind treatment or reported worsening of their NYHA class orpatient global assessment. Patients are considered unchanged if they areneither improved nor worsened.

Results:

LCZ696 was well tolerated with adverse effects similar to valsartan.

Of 301 patients, 261 patients completed evaluation at 12 weeks and 241patients at 36 weeks. The mean age was 71 years, 57% of patients werefemale, and the majority of patients were NYHA class II. Atrialfibrillation was present at baseline in 85 (28%) patients. Mean leftventricular ejection fraction (LVEF) was 58±7.7%, and LVEF was greaterthan 50% in 238 (87%) of patients. Blood pressure was well-controlled(mean sitting blood pressure 135/77 mm Hg, median sitting blood pressure136/79 mm Hg). Baseline NT-proBNP was elevated (geometric mean 830.6pg/mL, 95% Cl 744-928). All patients were on diuretics at baseline andthe majority of patients had been taking an ACE inhibitor or angiotensinreceptor blocker prior to enrollment. Echocardiographic assessment atbaseline demonstrated reduced mitral annular relaxation velocity,elevated E/e′, and enlarged left atria, consistent with mild elevationof cardiac filling pressures.

The primary endpoint, change in NT-proBNP from baseline to 12 weeks, wassignificantly different in the LCZ696 group compared with the valsartangroup (ratio of change LCZ696/valsartan 0.77, 95% Cl 0.64-0.92, p=0.005;see Table 1) with a greater reduction in the LCZ696-treated patients.

Analysis of the primary endpoint in completers only (p=0.007) or withmultiple imputation for missing values (p=0.01) yielded similar results.The effect of LCZ696 on NT-proBNP occurred fairly early, although anearly reduction in NT-proBNP after 4 weeks of treatment in the LCZ696group compared with the valsartan group was not significant (p=0.063).The reduction in NT-proBNP at 12 weeks was noted in all prespecifiedsubgroups. Of these subgroups, only patients with diabetes had adifferentially greater reduction in NT-proBNP when treated with LCZ696compared with patients without diabetes (interaction p=1.02).

TABLE 1 NT-proBNP at baseline, 12 weeks, and 36 weeks, and ratio ofchange in NT- proBNP at 12 and 36 weeks NT-proBNP (pg/ml) at 12 weeksNT-proBNP (pg/ml) at 36 weeks n Baseline 12 weeks n Baseline 36 weeksLCZ696 134 783 605 115 763 496 (670-914)  (512-714) (646-901) (401-613)Valsartan 132 862 835 116 822 607 (733-1012) (710-981) (688-983)(484-760) Ratio of change 0.77 (95% CI 0.85 (95% CI (LZC696/valsartan)0.64-0.92), 0.65-1.09), p = 0.005 p = 0.20 Data for NT-proBNP aregeometric mean (95% CI)

After 12 weeks of treatment, blood pressure was reduced by 9.3 (SD14)/4.9 (10) mm Hg in the LCZ696 group and 2.9 (17)/2.1 (11) mm Hg inthe valsartan group (p=0.001 for systolic and p=0.09 for diastolic bloodpressure differences). LCZ696 was associated with a greater reduction inNT-proBNP than was valsartan even after adjustment for the change inblood pressure between the two groups (p=0.01). Moreover, change inblood pressure correlated poorly with change in NT-proBNP (r=0.104,p=0.1).

Minimal changes in echocardiographic parameters such as left ventricularsize or function, diastolic function, left ventricular (LV) mass ortricuspid regurgitant velocity from baseline to 12 weeks betweentreatment groups has been observed. Left atrial dimension wasnumerically, but not significantly, reduced at 12 weeks.

Although NT-proBNP remained reduced from baseline at 36 weeks in theLCZ696 group (see Table 1), the difference between treatment groups at36 weeks was no longer significant (p=0.20; Table 1). At 36 weeks, bloodpressure was reduced by 7.5 (15)/5.1 (10.8) in the LCZ696 group versus1.5 (16)/0.34 (11.5) in the valsartan group (p=0.006 for systolic andp=0.001 for diastolic blood pressure differences).

Left atrial volume and left atrial volume index (LAVI) was reducedsignificantly in the LCZ696 group alter 36 weeks of treatment (p=0.003and 0.007, for left atrial volume and LAVI respectively), as was leftatrial dimension (p=0.034) (Table 2).

The change in left atrial size was most apparent in patients withoutatrial fibrillation at baseline. No other echocardiographic measures,including LVEF, ventricular volumes, left ventricular mass index,relative wall thickness, or measures of diastolic function, differedbetween treatment groups at 36 weeks.

TABLE 2 Changes in Echocardiographic Parameters at 36 weeks (Left atrialdimension (LA dimension), left atrial volume (LA Volume), left atrialvolume index (LA Volume Index), left ventricle mass index (LA massindex) and relative wall thickness) LCZ696 Valsartan Baseline Δ fromBaseline Δ from N Baseline N Baseline p-value LA dimension 99 3.68 −0.15108 3.73 −0.08 0.03 (cm) LA Volume (ml) 96 65.26 −4.61 112 68.28 0.370.003 LA Volume 90 35.01 −2.61 106 36.80 0.31 0.007 Index (ml/m²) LVmass index 91 76.56 −2.78 100 79.45 −1.93 0.35 (g/m²) Relative wall 980.37 +0.01 107 0.37 +0.01 0.96 thickness (%)

NYHA class improvement at 12 weeks did not differ significantly betweengroups (p=0.11), but we noted an improvement in NYHA class at 36 weeksin the LCZ696 group compared with the valsartan group (p=0.05, FIG. 1).

Clinical composite assessment after 12 weeks (p=0.19) and 36 weeks(p=0.17) of treatment did not differ significantly between groups (FIG.1). There was no difference in KCCQ score between treatment groups ateither time point.

Target dose was achieved in 121 (81%) patients in the LCZ696 group andin 119 (78%) in the valsartan group. The use of concomitantblood-pressure lowering drugs, particularly loop diuretics, was greaterin the valsartan group during the trial, although β-blocker use wassimilar. In the LCZ696 group, 22 patients (15%) had one or more seriousadverse events, including one death; in the valsartan group, 30 patients(20%) had one or more serious adverse events, including two deaths. Inthe valsartan group, the adverse event “atrial fibrillation” wasobserved in 8 patients (5.3%), whereas in the LCZ696 group, only 2patients (2.0%) experienced this adverse event.

The number of patients with hypotension, renal dysfunction, orhyperkalaemia did not differ between groups. Angio-oedema occurred inone patient on LCZ696, who did not need admission to hospital, and nopatients on valsartan.

CONCLUSION

In summary, in patients with heart failure with preserved ejectionfraction, the angiotensin receptor neprilysin inhibitor LCZ696 reducedNT-proBNP to a greater extent than valsartan after 12 weeks of therapy.The reduction in NT-proBNP in patients receiving LCZ696 became evidentat 4 weeks and was sustained to 36 weeks, though the between groupdifference was no longer statistically significant. We further observeda reduction in left atrial size, indicative of reverse left atrialremodeling, in patients randomized to LCZ696 after 36 weeks, comparedwith those randomized to valsartan. We observed trends in improvement inNYHA class in those patients randomized to LCZ696, which was overallwell-tolerated. These findings indicate that a NEP inhibitor may havefavorable effects in patients with HF-pEF.

In addition, the induction of reverse remodeling of the left atrium,i.e. the significant reductions in left atrial volume and left atrialdimension, upon treatment with LCZ696 provide a potential signal for theuse of LCZ696 for treatment or prevention of atrial fibrillation and/orthe reduction of new onset atrial fibrillation upon treatment withLCZ696 in comparison to other drugs currently being the standard ofcare. This hypothesis is further supported by the fact that theincidence of the adverse event atrial fibrillation was lower in theLCZ696 treated patient group than in the valsartan treated patientgroup.

Example 2

A randomized, double-blind, parallel group, active-controlled, two-arm,event-driven trial comparing the long-term efficacy and safety ofenalapril and LCZ696 on morbidity and mortality in patients with chronicsymptomatic heart failure and reduced ejection fraction (HF-REF)[PARADIGM-HF].

LCZ696: see Example 1

Enalapril

The ACE inhibitor Enalapril or(2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-pyrrolidine-2-carboxylicacid can be purchased from commercial sources or can be preparedaccording to known methods.

Objective & Methods:

Patients with chronic HF, NYHA functional class II-IV symptoms, anelevated plasma B-type natriuretic peptide (BNP) or NT-proBNP level and,initially, a left ventricular ejection fraction of ≤40% (later amendedto ≤35%) are eligible. Patients enter a single blind enalapril run-inperiod (titrated to 10 mg bid) which, depending on tolerability, isfollowed by an LCZ696 run-in period (100 mg titrated to 200 mg bid).Then, patients tolerating both drugs at the target dose, are randomized1:1 to either enalapril 10 mg bid or LCZ696 200 mg bid. The primaryoutcome is the composite of cardiovascular death or HF hospitalization,although the trial is powered to detect a 15% relative risk reduction incardiovascular death with LCZ696, compared with enalapril. Secondaryoutcome measures are change in the Kansas City CardiomyopathyQuestionnaire (KCCQ) clinical summary score at 8 months, change in renalfunction, and time to all-cause mortality.

Study Design and Procedures

Detailed study design and procedures can be found underwww.clinicaltrials.gov, study number NCT01035255, and as published inThe European Journal of Heart Failure by McMurray et al (18 Apr. 2013)fitted “Dual angiotensin receptor and neprilysin inhibition as analternative to angiotensin converting enzyme inhibition in patients withchronic systolic heart failure: rationale for and design of theProspective comparison of ARNI with ACEI to Determine Impact on GlobalMortality and morbidity in Heart Failure trial (PARADIGM-HF)”.

Example 3

A multicenter, randomized, double-blind, parallel group,active-controlled study to evaluate the efficacy and safety of LCZ696compared to valsartan, on morbidity and mortality in heart failurepatients (NYHA Class II-IV) with preserved ejection fraction[PARAGON-HF]

LCZ696: see Example 1

Valsartan: see Example 1

Background

Heart failure with preserved ejection fraction (HFpEF) accounts for upto half of heart failure (HF) cases and is associated with substantialmorbidity and mortality. To date both angiotensin converting enzymeinhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have beentested in clinical trials in HFpEF and not been shown to improve theprimary outcome. Several pathophysiologic mechanisms have beenimplicated in this disorder, including abnormalities of diastolicfunction and impaired natriuretic response to acute volume expansion.

LCZ696 is a first in class, angiotensin receptor neprilysin inhibitor(ARNI), providing systemic exposure to AHU377, a neprilysin (NEP)inhibitor and valsartan, an ARB. The potential clinical benefits fromNEP inhibition can only be leveraged if the RAAS system is inhibitedconcomitantly.1, 2

The mechanisms of action of LCZ696 suggest that it may have an impact onthe pathophysiology of HFpEF, in which it is believed that excessivefibrosis and myocyte hypertrophy lead to abnormal left ventricularrelaxation and filling, impaired diastolic distensibility and/orincreased vascular stiffness, with consequent elevated cardiac fillingpressures.

The PARAMOUNT trial tested the safety and efficacy of LCZ696 in patientswith HFpEF and showed a significant reduction in N-terminal pro-B-typenatriuretic peptide (NT-proBNP) at 12 weeks and significant improvementin left atrial size and New York Heart Association (NYHA) class inpatients randomized to LCZ696 compared to valsartan at 36 weeks.NT-proBNP is not a substrate for neprilysin.

Methods

-   -   PARAGON-HF will assess the effect of LCZ696 on outcomes        (cardiovascular [CV] death and total—first and recurrent—HF        hospitalizations) in patients with HFpEF.    -   Screening: up to 2 weeks    -   Active Run-In Period: 3-8 weeks (can be shorter for patients        previously exposed to standard doses of RAAS blockade; longer        for patients with no prior exposure or on low doses of ACE Is or        ARBs.)    -   Double Blind Period: Projected 2.75 years enrollment; with a        minimum of 2 years follow up        Primary and Secondary Objectives        Primary Objective:

The primary objective of this trial is to compare LCZ696 to valsartan inreducing the rate of the composite endpoint of CV death and total (firstand recurrent) HF hospitalizations, in HF patients (NYHA Class II-IV)with preserved EF (left ventricular ejection fraction [LVEF]≥45%).

Secondary Objectives:

-   -   To compare LCZ696 to valsartan in reducing the rate of the        composite endpoint of CV death, total HF hospitalizations, total        non-fatal strokes, and total non-fatal myocardial infarctions        (MIs). Total is defined as the first and all recurrent events.    -   To compare LCZ696 to valsartan in improving NYHA functional        classification at 8 months.    -   To compare LCZ696 to valsartan in delaying the time to new onset        AF in patients with no history of AF and without AF on        electrocardiogram (ECG) at baseline.    -   To compare LCZ696 to valsartan in delaying the time to all-cause        mortality.        Study Design and Detailed Procedures

Detailed study design and procedures can be found underwww.clinicaltrials.gov, study number NCT01920711.

The invention claimed is:
 1. A method for the treatment of heart failurewith preserved ejection fraction (HF-PEF) in a human patient comprisingadministration of a therapeutically effective amount of the NEPinhibitor pro-drugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester to the patient in need of such treatment, wherein theNEP inhibitor pro-drug is administered together with the AngiotensinReceptor Blocker valsartan in a 1:1 molar ratio in the form of LCZ696 astrisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-Z-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate.2. The method according to claim 1, wherein the method is for thetreatment of atrial fibrillation.
 3. The method according to claim 1,wherein the method is for the treatment of patients with no history ofatrial fibrillation.
 4. The method according to claim 1, wherein themethod is for the use of reducing the level of plasma NT-proBNP.
 5. Themethod according to claim 1, wherein the administration of the NEPinhibitor pro-drug or NEP inhibitor leads to a sustained reduction inplasma NT-proBNP concentration.
 6. The method according to claim 1,wherein the method is for the improvement, stabilization or delayedworsening in NYHA classification of patients suffering from heartfailure.
 7. The method according to claim 1 wherein LCZ696 isadministered twice daily at a dose of 50 mg, 100 mg, 200 mg or 400 mg.8. The method according to claim 1, wherein the treatment ischaracterized by the reduction of the left atrial volume, the leftatrial volume index (LAVI) and/or the left atrial dimension.